RIKEN Cluster for Pioneering Research, Tsukuba, Japan.
Department of Genome Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Genes Cells. 2019 Sep;24(9):627-635. doi: 10.1111/gtc.12713. Epub 2019 Jul 30.
Cellular senescence plays an important role in aging and is induced by cyclin-dependent kinase (Cdk) inhibitors that accumulate following stresses during aging. However, the underlying mechanism remains elusive. Herein, we demonstrate that activating transcription factor 7 (ATF7), the stress-responsive recruiter of histone H3K9 di- and trimethyltransferases, functions in the accumulation of Cdk inhibitors. Atf7-deficient (Atf7 ) mice have a shorter lifespan than wild-type (WT) mice. Levels of p16 Cdk inhibitor mRNA increased with age more rapidly in Atf7 mice than in WT animals. ATF7 binds to the p16 gene promoter and was released with age. Consistently, histone H3K9me2 levels on the p16 gene promoter were lower in Atf7 mice than in WT animals. Similar results were obtained when Atf7 and WT mouse embryonic fibroblasts (MEFs) were cultured under 20% oxygen conditions, which induces cellular senescence via oxidative stress. Phosphorylation of ATF7 by p38 was also increased with the passage of MEFs, consistent with previous observations that ATF7 phosphorylation by p38 induces its release from chromatin. These results indicate that stress-induced and ATF7-dependent epigenetic changes on p16 genes play an important role in cellular senescence.
细胞衰老在衰老过程中起着重要作用，是由衰老过程中因应激而积累的细胞周期蛋白依赖性激酶（Cdk）抑制剂诱导的。然而，其潜在的机制仍不清楚。在此，我们证明了激活转录因子 7（ATF7），一种应激反应性募集组蛋白 H3K9 二甲基和三甲基转移酶的物质，在 Cdk 抑制剂的积累中发挥作用。Atf7 缺陷（Atf7 ）小鼠的寿命比野生型（WT）小鼠短。在 Atf7 小鼠中，p16 Cdk 抑制剂 mRNA 的水平随年龄的增长比 WT 动物更快地增加。ATF7 与 p16 基因启动子结合，并随年龄的增长而释放。一致地，Atf7 小鼠中 p16 基因启动子上的组蛋白 H3K9me2 水平低于 WT 动物。当 Atf7 和 WT 小鼠胚胎成纤维细胞（MEF）在 20%氧气条件下培养时，也得到了类似的结果，这通过氧化应激诱导细胞衰老。MEF 传代时，ATF7 被 p38 磷酸化的程度也增加了，这与先前的观察结果一致，即 p38 磷酸化 ATF7 会导致其从染色质中释放出来。这些结果表明，应激诱导和 ATF7 依赖性的 p16 基因表观遗传变化在细胞衰老中起着重要作用。
